Session: Novel b-Lactams and b-Lactamase Inhibitors
Location:
Exhibit Hall
Session Date:
Sunday, 9/26/99
Session Time:
1:30 pm - 3:00 pm
Design, Synthesis, and SAR of Water-Soluble Dibasic Cephalosporins Active
against Resistant Gram-Positive Bacteria
A. Cho, M. Ludwikow, N. Liu, A. Fan, T. Glinka, Z.J. Zhang, M. Price, S.
Chamberland, V.J. Lee, S.J. Hecker
Microcide Pharmaceuticals: Mountain View, CA
We recently reported the discovery of MC-02,479, a new cephalosporin displaying
potent activity against sensitive and resistant Gram-positive organisms including
methicillin-resistant Staphylococcus aureus (MRSA) (Glinka, et al., 37th ICAAC,
Abstract #F176, 1997) The compound bears a basic 4-pyridyl group at the C(3)
position that is protonated at acidic pH, affording sufficient solubility for intravenous
administration. In the current work, we have explored other non-basic aromatic motifs at
C(3), which required appending an additional basic functionality within the structural
framework for solubilization. Several strategies were pursued, including modification of
the appendage on the C(3)-heterocycle, attachment of a basic group to the C(7)-oxime,
and replacement of the C(7)-heterocycle. The latter approach afforded MC-03,260,
which displays excellent solubility (>20 mg/ml at pH 4.5) while retaining good potency
(MIC90 vs. MRSA 4 mg/ml, ED50 against S. aureus Smith 0.3 mg/kg). |
